X-129567266-C-T

Variant names:

• chrX-129567266-C-T
• rs137853839
• NM_000276.4:c.1369C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000276.4(OCRL):​c.1369C>T​(p.Arg457Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000185 in 1,082,057 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R457G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: OCRL NM_000276.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.78
• Publications: 0 publications found

Genes affected

OCRL (HGNC:8108): (OCRL inositol polyphosphate-5-phosphatase) This gene encodes an inositol polyphosphate 5-phosphatase. This protein is involved in regulating membrane trafficking and is located in numerous subcellular locations including the trans-Golgi network, clathrin-coated vesicles and, endosomes and the plasma membrane. This protein may also play a role in primary cilium formation. Mutations in this gene cause oculocerebrorenal syndrome of Lowe and also Dent disease. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

OCRL Gene-Disease associations (from GenCC):

• Dent disease type 2

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• oculocerebrorenal syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Laboratory for Molecular Medicine, Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000276.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OCRL	NM_000276.4	MANE Select	c.1369C>T	p.Arg457Cys	missense	Exon 14 of 24	NP_000267.2
	OCRL	NM_001318784.2		c.1372C>T	p.Arg458Cys	missense	Exon 14 of 24	NP_001305713.1
	OCRL	NM_001587.4		c.1369C>T	p.Arg457Cys	missense	Exon 14 of 23	NP_001578.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OCRL	ENST00000371113.9	TSL:1 MANE Select	c.1369C>T	p.Arg457Cys	missense	Exon 14 of 24	ENSP00000360154.4	Q01968-1
	OCRL	ENST00000357121.5	TSL:1	c.1369C>T	p.Arg457Cys	missense	Exon 14 of 23	ENSP00000349635.5	Q01968-2
	OCRL	ENST00000949289.1		c.1366C>T	p.Arg456Cys	missense	Exon 14 of 24	ENSP00000619348.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000185 AC: 2 AN: 1082057 Hom.: 0 Cov.: 27 AF XY: 0.00000286 AC XY: 1 AN XY: 349667

African (AFR) AF: 0.00 AC: 0 AN: 26076

American (AMR) AF: 0.00 AC: 0 AN: 35181

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19262

East Asian (EAS) AF: 0.00 AC: 0 AN: 30126

South Asian (SAS) AF: 0.00 AC: 0 AN: 53748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40519

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4102

European-Non Finnish (NFE) AF: 0.00000242 AC: 2 AN: 827484

Other (OTH) AF: 0.00 AC: 0 AN: 45559

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Lowe syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.026	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.71		Loss of MoRF binding (P = 0.0253)
MVP		0.97
MPC		2.7
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.88
gMVP		0.94
Mutation Taster		=37/63	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs137853839; hg19: chrX-128701243; COSMIC: COSV63979992;